In 1931, Otto Warburg was awarded the Nobel Prize in medicine for his pioneering work demonstrating glycolysis as the primary anaerobic glucose metabolism within cancer cells (Warburg O W F, Negelein E., J Gen Physiol. 1927; 8:519-530). Unfortunately, to date, a universal therapy has not emerged from his work. Since that time, it has become apparent that not all cancer cells utilize glycolysis to produce ATP, but some utilize oxidative phosphorylation (Krebs cycle) to generate energy (Seyfried T N, Shelton L M. Nutr Metab (Lond). 2010; 7:7). More specifically, those cells in the interior of a tumor where the oxygen tension is lowest and the milieu more acidotic tend to utilize glycolysis while those cells in the periphery where oxygen tension is higher tend to utilize oxidative phosphorylation (Vaupel P. Semin Radiat Oncol. July 2004; 14(3):198-206), Glycolysis generates protons that need to be transported out of the cell to avoid acid build up. Many of the hydrogen ions that are transported out of the cell are accompanied by lactate to maintain electrical neutrality. There are other mechanisms exclusive of lactate that generate anions to buffer the acid production of glycolysis. These include metabolism of pyruvate to bicarbonate by hydration of CO2 catalyzed by various carbonic anhydrases and monocarboxylases (Halestrap A P. UCSD-Nature Molecule Pages. 29 Oct. 2009:1-20). Decreasing the intracellular lactate concentration may cause cell death from unchecked acidosis. The intracellular pHs of the interior and exterior tumor cells are similar but the extracellular fluid surrounding the inner cells is orders of magnitude more acidic (Gerweck L E, et al. Mol Cancer Ther. May 2006; 5(5):1275-1279). It has been shown that a lactate shuttle exists between inner and outer cells where lactate is converted to pyruvate in the outer cells and then metabolized by oxidative phosphorylation to produce ATP to sustain cancer cells (Brooks G A. J. Physiol. Dec. 1, 2009; 587(Pt 23):5591-5600).
The explanation of which tumor cells utilize glycolysis is more complex than oxygen availability. Rapid rates of energy production require the expedient but inefficient fermentation of glucose if there are insufficient or functionally abnormal mitochondria to process glucose through oxidative phosphorylation (Seyfried T N, Shelton L M. Nutr Metab (Lond). 2010; 7:7). In addition to the metabolic effects of lactate in glycolysis, lactate has also been shown to contribute to tumor cell invasion and increased cell motility (Gatenby R A, et al. Cancer Res. May 15, 2006; 66(10):5216-5223).
More recent investigations have tried to separate lactate production from the hypoxic effects on tumor growth by using genetic markers. These studies suggest lactic acidosis may be independent of oxygen tension and may be associated with a more favorable clinical outcome (Chen J L, et al. PLoS Genet, December 2008; 4(12):e1000293). If this concept is true, then inactivation or trapping of lactate could worsen clinical outcome.
One major problem associated with present medications that target tumor metabolism is that they also target normal cells. The compositions of the invention solves the problem in the art. The compositions of the invention are tumoricidal and has the advantage that it is less harmful to cells having mitochondria with the capacity to shuttle pyruvate than the subset of cancer cells that exclusively utilize glycolysis.